To highlight individual and neighborhood interactions in the risk of adolescent substance use, this study examined the moderating role of neighborhood disadvantage on the relationship between pubertal development and adolescent girls’ substance use. Drawing on the contextual amplification hypothesis, it was hypothesized that the effect of pubertal development on substance use would vary by level of neighborhood disadvantage and race. The sample included 5,591 adolescent girls from the National Longitudinal Study of Adolescent Health (23% Black, 15% Hispanic, 55% White, and 7% Other race). Results showed that the relationships between pubertal development, neighborhood disadvantage, and alcohol use varied for girls from different racial backgrounds. Although there was some of evidence of contextual amplification among Black adolescent girls, low levels of neighborhood disadvantage tended to be associated with higher levels of alcohol use during early adolescence. Findings highlight the importance of studying the interaction between individual- and environmental-level risk factors.